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      Phytochemicals: Potential Lead Molecules for MDR Reversal

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          Abstract

          Multidrug resistance (MDR) is one of the main impediments in the treatment of cancers. MDR cancer cells are resistant to multiple anticancer drugs. One of the major mechanisms of MDR is the efflux of anticancer drugs by ABC transporters. Increased activity and overexpression of these transporters are important causes of drug efflux and, therefore, resistance to cancer chemotherapy. Overcoming MDR is a fundamental prerequisite for developing an efficient treatment of cancer. To date, various types of ABC transporter inhibitors have been employed but no effective anticancer drug is available at present, which can completely overcome MDR. Phytochemicals can reverse MDR in cancer cells via affecting the expression or activity of ABC transporters, and also through exerting synergistic interactions with anticancer drugs by addressing additional molecular targets. We have listed numerous phytochemicals which can affect the expression and activity of ABC transporters in MDR cancer cell lines. Phytochemicals in the groups of flavonoids, alkaloids, terpenes, carotenoids, stilbenoids, lignans, polyketides, and curcuminoids have been examined for MDR-reversing activity. The use of MDR-reversing phytochemicals with low toxicity to human in combination with effective anticancer agents may result in successful treatment of chemotherapy-resistant cancer. In this review, we summarize and discuss published evidence for natural products with MDR modulation abilities.

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          Drug resistance and combating drug resistance in cancer

          Cancer is the second leading cause of death in the US. Current major treatments for cancer management include surgery, cytotoxic chemotherapy, targeted therapy, radiation therapy, endocrine therapy and immunotherapy. Despite the endeavors and achievements made in treating cancers during the past decades, resistance to classical chemotherapeutic agents and/or novel targeted drugs continues to be a major problem in cancer therapies. Drug resistance, either existing before treatment (intrinsic) or generated after therapy (acquired), is responsible for most relapses of cancer, one of the major causes of death of the disease. Heterogeneity among patients and tumors, and the versatility of cancer to circumvent therapies make drug resistance more challenging to deal with. Better understanding the mechanisms of drug resistance is required to provide guidance to future cancer treatment and achieve better outcomes. In this review, intrinsic and acquired resistance will be discussed. In addition, new discoveries in mechanisms of drug resistance will be reviewed. Particularly, we will highlight roles of ATP in drug resistance by discussing recent findings of exceptionally high levels of intratumoral extracellular ATP as well as intracellular ATP internalized from extracellular environment. The complexity of drug resistance development suggests that combinational and personalized therapies, which should take ATP into consideration, might provide better strategies and improved efficacy for fighting drug resistance in cancer.
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            Modes of Action of Herbal Medicines and Plant Secondary Metabolites

            Plants produce a wide diversity of secondary metabolites (SM) which serve them as defense compounds against herbivores, and other plants and microbes, but also as signal compounds. In general, SM exhibit a wide array of biological and pharmacological properties. Because of this, some plants or products isolated from them have been and are still used to treat infections, health disorders or diseases. This review provides evidence that many SM have a broad spectrum of bioactivities. They often interact with the main targets in cells, such as proteins, biomembranes or nucleic acids. Whereas some SM appear to have been optimized on a few molecular targets, such as alkaloids on receptors of neurotransmitters, others (such as phenolics and terpenoids) are less specific and attack a multitude of proteins by building hydrogen, hydrophobic and ionic bonds, thus modulating their 3D structures and in consequence their bioactivities. The main modes of action are described for the major groups of common plant secondary metabolites. The multitarget activities of many SM can explain the medical application of complex extracts from medicinal plants for more health disorders which involve several targets. Herbal medicine is not a placebo medicine but a rational medicine, and for several of them clinical trials have shown efficacy.
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              The flavonoid biosynthetic pathway in plants: Function and evolution

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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                19 June 2020
                2020
                : 11
                : 832
                Affiliations
                [1] 1Institute of Pharmacy and Molecular Biotechnology, Heidelberg University , Heidelberg, Germany
                [2] 2Marine Sciences Faculty, Tarbiat Modares University , Noor, Iran
                Author notes

                Edited by: Maria José U. Ferreira, University of Lisbon, Portugal

                Reviewed by: Olga Wesolowska, Wroclaw Medical University, Poland; Mariana A. Reis, University of Porto, Portugal

                *Correspondence: Michael Wink, wink@ 123456uni-heidelberg.de

                This article was submitted to Ethnopharmacology, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2020.00832
                7317022
                32636741
                4872337e-32d8-4aa3-814e-fa2fccb4d13a
                Copyright © 2020 Tinoush, Shirdel and Wink

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 20 December 2019
                : 20 May 2020
                Page count
                Figures: 5, Tables: 2, Equations: 0, References: 212, Pages: 35, Words: 17467
                Categories
                Pharmacology
                Review

                Pharmacology & Pharmaceutical medicine
                cancer,abc-transporter,drug efflux,multidrug resistance,secondary metabolites,synergism

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